Predictions of Bedaquiline and Pretomanid Target Attainment in Lung Lesions of Tuberculosis Patients using Translational Minimal Physiologically Based Pharmacokinetic Modeling
© 2023. The Author(s)..
BACKGROUND: Site-of-action concentrations for bedaquiline and pretomanid from tuberculosis patients are unavailable. The objective of this work was to predict bedaquiline and pretomanid site-of-action exposures using a translational minimal physiologically based pharmacokinetic (mPBPK) approach to understand the probability of target attainment (PTA).
METHODS: A general translational mPBPK framework for the prediction of lung and lung lesion exposure was developed and validated using pyrazinamide site-of-action data from mice and humans. We then implemented the framework for bedaquiline and pretomanid. Simulations were conducted to predict site-of-action exposures following standard bedaquiline and pretomanid, and bedaquiline once-daily dosing. Probabilities of average concentrations within lesions and lungs greater than the minimum bactericidal concentration for non-replicating (MBCNR) and replicating (MBCR) bacteria were calculated. Effects of patient-specific differences on target attainment were evaluated.
RESULTS: The translational modeling approach was successful in predicting pyrazinamide lung concentrations from mice to patients. We predicted that 94% and 53% of patients would attain bedaquiline average daily PK exposure within lesions (Cavg-lesion) > MBCNR during the extensive phase of bedaquiline standard (2 weeks) and once-daily (8 weeks) dosing, respectively. Less than 5% of patients were predicted to achieve Cavg-lesion > MBCNR during the continuation phase of bedaquiline or pretomanid treatment, and more than 80% of patients were predicted to achieve Cavg-lung >MBCR for all simulated dosing regimens of bedaquiline and pretomanid.
CONCLUSIONS: The translational mPBPK model predicted that the standard bedaquiline continuation phase and standard pretomanid dosing may not achieve optimal exposures to eradicate non-replicating bacteria in most patients.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:62 |
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| Enthalten in: |
Clinical pharmacokinetics - 62(2023), 3 vom: 27. März, Seite 519-532 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mehta, Krina [VerfasserIn] |
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| Links: |
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| Themen: |
2KNI5N06TI |
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| Anmerkungen: |
Date Completed 25.08.2023 Date Revised 25.08.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s40262-023-01217-7 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM353085030 |
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| 245 | 1 | 0 | |a Predictions of Bedaquiline and Pretomanid Target Attainment in Lung Lesions of Tuberculosis Patients using Translational Minimal Physiologically Based Pharmacokinetic Modeling |
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| 500 | |a Date Revised 25.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s). | ||
| 520 | |a BACKGROUND: Site-of-action concentrations for bedaquiline and pretomanid from tuberculosis patients are unavailable. The objective of this work was to predict bedaquiline and pretomanid site-of-action exposures using a translational minimal physiologically based pharmacokinetic (mPBPK) approach to understand the probability of target attainment (PTA) | ||
| 520 | |a METHODS: A general translational mPBPK framework for the prediction of lung and lung lesion exposure was developed and validated using pyrazinamide site-of-action data from mice and humans. We then implemented the framework for bedaquiline and pretomanid. Simulations were conducted to predict site-of-action exposures following standard bedaquiline and pretomanid, and bedaquiline once-daily dosing. Probabilities of average concentrations within lesions and lungs greater than the minimum bactericidal concentration for non-replicating (MBCNR) and replicating (MBCR) bacteria were calculated. Effects of patient-specific differences on target attainment were evaluated | ||
| 520 | |a RESULTS: The translational modeling approach was successful in predicting pyrazinamide lung concentrations from mice to patients. We predicted that 94% and 53% of patients would attain bedaquiline average daily PK exposure within lesions (Cavg-lesion) > MBCNR during the extensive phase of bedaquiline standard (2 weeks) and once-daily (8 weeks) dosing, respectively. Less than 5% of patients were predicted to achieve Cavg-lesion > MBCNR during the continuation phase of bedaquiline or pretomanid treatment, and more than 80% of patients were predicted to achieve Cavg-lung >MBCR for all simulated dosing regimens of bedaquiline and pretomanid | ||
| 520 | |a CONCLUSIONS: The translational mPBPK model predicted that the standard bedaquiline continuation phase and standard pretomanid dosing may not achieve optimal exposures to eradicate non-replicating bacteria in most patients | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Antitubercular Agents |2 NLM | |
| 650 | 7 | |a bedaquiline |2 NLM | |
| 650 | 7 | |a 78846I289Y |2 NLM | |
| 650 | 7 | |a Nitroimidazoles |2 NLM | |
| 650 | 7 | |a pretomanid |2 NLM | |
| 650 | 7 | |a Pyrazinamide |2 NLM | |
| 650 | 7 | |a 2KNI5N06TI |2 NLM | |
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| 700 | 1 | |a van der Graaf, Piet H |e verfasserin |4 aut | |
| 700 | 1 | |a van Hasselt, J G Coen |e verfasserin |4 aut | |
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